Diabetes Mellitus (DM) is a chronic, systemic, metabolic disease caused by the long-term interaction of genetic factors and environmental factors. It is characterized by increased plasma glucose levels, and is a disease affecting normal physiological activities resulted from the metabolic disorder of sugar, fat and protein mainly caused by insufficient insulin secretion or dysfunction (insulin resistance) in the body. Complications of diabetes can be divided into acute complications and chronic complications, in which, acute complications include diabetic ketoacidosis, diabetic hyperosmolar coma, various acute infections and lactic acidosis etc. (hypoglycemia that occurs during the treatment of diabetes is also one of the most common acute complications); and chronic complications include diabetic eye disease, diabetic nephropathy, diabetic neuropathy, diabetic cardio-cerebral limb vascular disease, diabetic foot and skin diseases and the like. The main clinical manifestations of diabetes are polydipsia, polyuria, polyphagia and weight loss and the like.
Diabetes is divided into Insulin-Dependent Diabetes Mellitus (IDDM, i.e. type I diabetes) and Non insulin-Dependent Diabetes Mellitus (NIDDM, i.e. type II diabetes), in which type II diabetes is the most common, accounting for more than 90% of people with diabetes. The exact etiology and pathogenesis of type I diabetes is still not well understood, and it is caused by the combination of genetic and environmental factors, mainly due to the destruction of islet β-cells in the body, which leads to the inability to produce insulin in the body. Patients need to be injected with insulin daily to control their insulin level in blood. Type II diabetes is a type of metabolic syndrome that can not control blood glucose levels in the body. It is mainly characterized by hyperglycemia, insulin resistance and insufficient insulin secretion. The cause of type II diabetes is mainly due to insulin resistance, which makes the body unable to use insulin effectively, or the reduction in insulin secretion so that the needs of the body cannot be met. Because such patients with diabetes can secrete insulin, insulin therapy is generally not required, and blood glucose can be controlled only by dietary adjustment or oral hypoglycemic agents.
The drugs currently available for the treatment of type II diabetes mainly include insulin and its analogues, sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, Glucagon-Like peptide-1 (GLP-1) analog, dipeptidyl peptidase IV (DPP IV) inhibitor, and the like. Although existing drugs can control blood sugar levels and reduce the incidence of complications, most of them have serious side effects such as gastrointestinal toxicity, weight gain, edema, and hypoglycemia etc. Therefore, the treatment of type II diabetes is still a difficult problem. Finding and developing therapeutic drugs with novel mechanism of action and small side effects has become a hot spot to which both academic and industrial circles have paid attention and to be solved.
DPP IV inhibitors can significantly reduce blood glucose levels in the body, increase glucose tolerance, promote insulin secretion, reduce glucagon levels, delay insulin resistance and increase response level of insulin in patients with type II diabetes when blood glucose increases. Compared with existing oral diabetes drugs, DPP IV inhibitors have following characteristics: (1) DPP IV inhibitors do not require injections, and can continuously reduce glycosylated hemoglobin levels by oral administration; (2) long-term use of DPP IV inhibitors have good tolerance; (3) insulin secretion and the release of glucagon can be improved; (4) insulin sensitivity can be improved, while increasing pancreatic β cell function; (5) incidence of hypoglycemia is lower, and weight gain, nausea, vomiting and gastrointestinal dysfunction won't occur; (6) DPP IV inhibitors have synergistic effects when used in combination with other type II diabetes drugs.
(R)-methyl 2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene[3,2-d]pyrimidine-6-carboxylic acid (compound of formula I) is a novel DPP IV inhibitor with strong hypoglycemic activity in vivo. However, the overall performance of (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene[3,2-d]pyrimidine-6-carboxylic acid in the existing form of free base is not satisfactory.
Therefore, there is an urgent need in the art to develop a polymorph of (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene[3,2-d]pyrimidine-6-carboxylic acid maleate (a compound of formula I) which is highly efficient, low toxicity and long-acting, the preparation method thereof is simple, thermal stability is good, hygroscopicity is low and the polymorph can be produced on a large scale to obtain pharmaceutically active ingredients with better performance.